Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance

Abstract

Post-extravasation survival is a key rate-limiting step of metastasis; however, not much is known about the factors that enable survival of the metastatic cancer cell at the secondary site. Furthermore, metastatic nodules are often refractory to current therapies, necessitating the elucidation of molecular changes that affect the chemosensitivity of metastases. Drug resistance exhibited by tumor spheroids has been shown to be mediated by cell adhesion and can be abrogated by addition of E-cadherin blocking antibody. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin in breast and prostate cancer cells. In this study, we show that this E-cadherin re-expression confers a survival advantage, particularly in the liver microenvironment. E-cadherin re-expression in MDA-MB-231 breast cancer cells resulted in increased attachment to hepatocytes. This heterotypic adhesion between cancer cells and secondary organ parenchymal cells activated ERK MAP kinase, suggesting a functional pro-survival role for E-cadherin during metastatic colonization of the liver. In addition, breast cancer cells that re-expressed E-cadherin in hepatocyte coculture were more chemoresistant compared to 231-shEcad cells unable to re-express E-cadherin. Similar results were obtained in DU-145 prostate cancer cells induced to re-express E-cadherin in hepatocyte coculture or following chemical induction by the GnRH agonist buserelin or the EGFR inhibitor PD153035. These results suggest that E-cadherin re-expression and other molecular changes imparted by a partial mesenchymal to epithelial reverting transition at the secondary site increase post-extravasation survival of the metastatic cancer cell and may help to elucidate why chemotherapy commonly fails to treat metastatic breast cancer.

The Mitogen-activated Protein (MAP) Kinases p38 and Extracellular Signal-regulated Kinase (ERK) Are Involved in Hepatocyte-mediated Phenotypic Switching in Prostate Cancer Cells

“…We have reported that hepatocyte co-culture can lead to up-regulation or re-expression of E-cadherin even in highly aggressive carcinoma cells (12,13). Herein, we show that this phenotypic switch extends to other epithelial markers of cell-cell cohesion including ZO-1 and connexin 43 (Fig.…”

“…We have previously shown that E-cadherin expression in prostate cancer metastases is inversely correlated with the size of metastasis (13), suggesting a metastable nature to the reversion toward an epithelial phenotype. To explore the relationship between the colony size and E-cadherin expression patterns in vitro, the cell number per colony with different E-cadherin expression levels was determined.…”

“…1 interaction extant in the liver microenvironment, it has been demonstrated that primary hepatocytes elicit E-cadherin cell surface expression in prostate carcinoma cells concomitant with down-regulation of EGFR signaling (12). These hepatocyte-induced E-cadherin re-expression in prostate and breast cancer cells increases the chemoresistant (13). EGFR activates several signaling cascades such as mitogenactivated protein kinases (MAPKs), PI3K-AKT, and JAK pathways.…”

Le microenvironnement tumoral et la résistance thérapeutique

“…Par exemple, l'adhérence de cellules tumorales myélomateuses aux cellules stromales de la moelle osseuse par l'intermédiaire de l'intégrine 1 stimule leur production d'interleukine-6 (IL-6) qui, à son tour, protège les cellules cancéreuses [9]. Ces cellules cancéreuses, mises en contact avec des hépatocytes, expriment de nouveau la E-cadhérine, favorisant leur chimiorésistance [10]. Le contact entre les cellules leucémiques et la niche de la moelle osseuse favorise leur résistance aux inhibiteurs de kinases, comme le sorafenib et le SU5614 [11].…”

Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

“…In addition to microenvironmental drivers of EMT, there is also evidence that MET in metastatic colonization may be mediated by the microenvironment. For example, DU-145 cells re-express Ecadherin upon coculture with human hepatocytes, and reexpression of E-cadherin also leads to chemoresistance, suggesting that MET may serve a protective role against chemotherapeutics at metastatic sites [152]. Similarly, coculture of DU-145 and PC-3 cells with primary rat hepatocytes leads to re-expression of E-cadherin and cytokeratin and reduced levels of vimentin [153], and coculture of ARCaP M cells with bone marrow stromal cells results in re-expression of Ecadherin in the ARCaP M cells [154], lending further support for the idea that microenvironmental cues at the sites of metastatic dissemination may lead to MET.…”